Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future

Abstract

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime.

Keywords: Gonadotropins; Hypogonadism; Infertility; Kallmann syndrome; Olfaction disorders; Puberty.

Fig. 1. The hypothalamic-pituitary-gonadal (HPG) axis. During early brain development, gonadotrophin-releasing hormone (GnRH)-releasing neurons (green) migrate from the nasal region to the hypothalamus, where they permanently reside and differentiate. Hypothalamic GnRH neurons secrete GnRH at the median eminence into the hypophyseal portal system and release pulsatile GnRH to the anterior pituitary. GnRH then binds to GnRH receptor 1 on the gonadotrophs to stimulate these cells to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which enter the systemic blood stream through the hypophyseal veins. LH and FSH act on the gonads (Sertoli and Leydig cells in testes and cumulus, mural and thecal cells in ovaries) to induce steroidogenesis and germ cell production which, in turn, maintains sexual competence. The release of kisspeptin from the hypothalamic neurons located in the arcuate (ARC) and anteroventral periventricular nuclei within the preoptic area is critically important for the re-initiation of pulsatile GnRH secretion at puberty. The developmental failure or misregulation of any one or combination of the genes involved in GnRH migration, secretion, and activity at any stage of development may result in congenital hypogonadotropic hypogonadism and Kallmann syndrome. AVPV, anteroventral periventricular nucleus.